Demographic, clinical and neuroimaging markers of post-stroke emotionalism: A preliminary investigation.

INTRODUCTION: Post stroke emotionalism (PSE) is a common but poorly understood condition. The value of altered brain structure as a putative risk factor for PSE alongside routinely available demographic and clinical variables has yet to be elucidated. METHODS: 85 patients were recruited from acute inpatient settings within 2 weeks of stroke. PSE was diagnosed using a validated semi-structured interview and standardised measures of stroke severity, functional ability, cognition, mood and quality of life were obtained. Neuroimaging variables (intracranial volume and volumes of cortical grey matter, subcortical grey matter, normal appearing white matter, cerebrum, cerebrospinal fluid and stroke; white matter hyperintensities; and mean cortical thickness) were derived using standardised methods from Magnetic Resonance Imaging (MRI) studies. The relationships between PSE diagnosis, brain structure, demographic and clinical variables were investigated using machine learning algorithms to determine how well different sets of predictors could classify PSE. RESULTS: The model with the best performance was derived from neuroradiological variables alone (sensitivity = 0.75; specificity = 0.8235), successfully classifying 9/12 individuals with PSE and 28/34 non-PSE cases. CONCLUSIONS: Neuroimaging measures appear to be important in PSE. Future work is needed to determine which specific variables are key. Imaging may complement standard behavioural measures and aid clinicians and researchers.

A Comparison of CVR Magnitude and Delay Assessed at 1.5 and 3T in Patients With Cerebral Small Vessel Disease.

BACKGROUND: Cerebrovascular reactivity (CVR) measures blood flow change in response to a vasoactive stimulus. Impairment is associated with several neurological conditions and can be measured using blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI). Field strength affects the BOLD signal, but the effect on CVR is unquantified in patient populations. METHODS: We recruited patients with minor ischemic stroke and assessed CVR magnitude and delay time at 3 and 1.5 Tesla using BOLD MRI during a hypercapnic challenge. We assessed subcortical gray (GM) and white matter (WM) differences using Wilcoxon signed rank tests and scatterplots. Additionally, we explored associations with demographic factors, WM hyperintensity burden, and small vessel disease score. RESULTS: Eighteen of twenty patients provided usable data. At 3T vs. 1.5T: mean CVR magnitude showed less variance (WM 3T: 0.062 ± 0.018%/mmHg, range 0.035, 0.093; 1.5T: 0.057 ± 0.024%/mmHg, range 0.016, 0.094) but was not systematically higher (Wilcoxon signal rank tests, WM: r = -0.33, confidence interval (CI): -0.013, 0.003, p = 0.167); delay showed similar variance (WM 3T: 40 ± 12 s, range: 12, 56; 1.5T: 31 ± 13 s, range 6, 50) and was shorter in GM (r = 0.33, CI: -2, 9, p = 0.164) and longer in WM (r = -0.59, CI: -16, -2, p = 0.010). Patients with higher disease severity tended to have lower CVR at 1.5 and 3T. CONCLUSION: Mean CVR magnitude at 3T was similar to 1.5T but showed less variance. GM/WM delay differences may be affected by low signal-to-noise ratio among other factors. Although 3T may reduce variance in CVR magnitude, CVR is readily assessable at 1.5T and reveals comparable associations and trends with disease severity.

Small vessel disease is associated with altered cerebrovascular pulsatility but not resting cerebral blood flow.

Cerebral small vessel disease (SVD) contributes to 25% of ischemic strokes and 45% of dementias. We aimed to investigate the role of cerebral blood flow (CBF) and intracranial pulsatility in SVD. We scanned 60 patients with minor ischemic stroke, representing a range of white matter hyperintensities (WMH). We rated WMH and perivascular spaces (PVS) using semi-quantitative scales and measured WMH volume. We measured flow and pulsatility in the main cerebral vessels and cerebrospinal fluid (CSF) using phase-contrast MRI. We investigated the association between flow, pulsatility and SVD features. In 56/60 patients (40 male, 67.8±8.3 years) with complete data, median WMH volume was 10.7 mL (range 1.4-75.0 mL), representing median 0.77% (0.11-5.17%) of intracranial volume. Greater pulsatility index (PI) in venous sinuses was associated with larger WMH volume (e.g. superior sagittal sinus, ß = 1.29, P < 0.01) and more basal ganglia PVS (e.g. odds ratio = 1.38, 95% confidence interval 1.06, 1.79, per 0.1 increase in superior sagittal sinus PI) independently of age, sex and blood pressure. CSF pulsatility and CBF were not associated with SVD features. Our results support a close association of SVD features with increased intracranial pulsatility rather than with low global CBF, and provide potential targets for mechanistic research, treatment and prevention of SVD.

Xanthine oxidase inhibition for the improvement of long-term outcomes following ischaemic stroke and transient ischaemic attack (XILO-FIST) - Protocol for a randomised double blind placebo-controlled clinical trial.

BACKGROUND: Allopurinol, a xanthine oxidase inhibitor, reduced progression of carotid-intima media thickness and lowered blood pressure in a small clinical trial in people with ischaemic stroke. Xanthine oxidase inhibition for improvement of long-term outcomes following ischaemic stroke and transient ischaemic attack (XILO-FIST) aims to assess the effect of allopurinol treatment on white matter hyperintensity progression and blood pressure after stroke. This paper describes the XILO-FIST protocol. METHODS: XILO-FIST is a multicentre randomised double-blind, placebo-controlled, parallel group clinical trial funded by the British Heart Foundation and the Stroke Association. The trial has been adopted by the Scottish Stroke Research Network and the UK Clinical Research Network. The trial is registered in clinicaltrials.gov (registration number NCT02122718). XILO-FIST will randomise 464 participants, aged greater than 50 years, with ischaemic stroke within the past month, on a 1:1 basis, to two years treatment with allopurinol 300 mg twice daily or placebo. Participants will undergo brain magnetic resonance imaging, cognitive assessment, ambulatory blood pressure monitoring and blood sampling at baseline and after two years treatment. The primary outcome will be white matter hyperintensity progression, measured using the Rotterdam progression scale. Secondary outcomes will include change in white matter hyperintensity volume, mean day-time systolic blood pressure and measures of cognitive function. Up to 100 will undergo additional cardiac magnetic resonance imaging in a sub-study of left ventricular mass. DISCUSSION: If white matter hyperintensity progression is reduced, allopurinol could be an effective preventative treatment for patients with ischaemic stroke and clinical endpoint studies would be needed. If allopurinol reduces blood pressure after stroke, then it could be used to help patients reach blood pressure targets.

Characterisation of tissue-type metabolic content in secondary progressive multiple sclerosis: a magnetic resonance spectroscopic imaging study.

Proton magnetic resonance spectroscopy yields metabolic information and has proved to be a useful addition to structural imaging in neurological diseases. We applied short-echo time Spectroscopic Imaging in a cohort of 42 patients with secondary progressive multiple sclerosis (SPMS). Linear modelling with respect to brain tissue type yielded metabolite levels that were significantly different in white matter lesions compared with normal-appearing white matter, suggestive of higher myelin turnover (higher choline), higher metabolic rate (higher creatine) and increased glial activity (higher myo-inositol) within the lesions. These findings suggest that the lesions have ongoing cellular activity that is not consistent with the usual assumption of 'chronic' lesions in SPMS, and may represent a target for repair therapies.

Predictors of gait speed and its change over three years in community-dwelling older people.

We aimed to assess whether and how changes in brain volume and increases in white matter hyperintensity (WMH) volume over three years predict gait speed and its change independently of demographics, vascular risk factors and physical status. We analyzed 443 individuals from the Lothian Birth Cohort 1936, at mean age 73 and 76 years. Gait speed at age 76 was predicted by age, grip strength and body mass index at mean age 73, three-year brain volume decrease and WMH volume increase, explaining 26.1% of variance. Decline in gait speed to age 76 was predicted by the same five variables explaining 40.9% of variance. In both analyses, grip strength and body mass index explained the most variance. A clinically significant decline in gait speed (≥ 0.1 m/s per year) occurred in 24.4%. These individuals had more structural brain changes. Brain volume and WMH changes were independent predictors of gait dysfunction and its three-year change, but the impact of malleable physical factors such as grip strength or body mass index was greater.

Blood pressure variability and leukoaraiosis in acute ischemic stroke.

Higher blood pressure, blood pressure variability, and leukoaraiosis are risk factors for early adverse events and poor functional outcome after ischemic stroke, but prior studies differed on whether leukoaraiosis was associated with blood pressure variability, including in ischemic stroke. In the Third International Stroke Trial, blood pressure was measured in the acute phase of ischemic stroke immediately prior to randomization, and at 0.5, 1, and 24 h after randomization. Masked neuroradiologists rated index infarct, leukoaraiosis, and atrophy on CT using validated methods. We characterized blood pressure variation by coefficient of variance and three other standard methods. We measured associations between blood pressure, blood pressure variability, and leukoaraiosis using generalized estimating equations, adjusting for age, and a number of covariates related to treatment and stroke type/severity. Among 3017 patients, mean (±SD) systolic and diastolic blood pressure decreased from 155(±24)/82(±15) mmHg pre-randomization to 146(±23)/78(±14) mmHg 24 h later ( P < 0.005). Mean within-subject coefficient of variance was 0.09 ± 0.05 for systolic and 0.11 ± 0.06 for diastolic blood pressure. Patients with most leukoaraiosis were older and had higher blood pressure than those with least ( P < 0.0001). Although statistically significant in simple pairwise comparisons, no measures of blood pressure variability were associated with leukoaraiosis when adjusting for confounding variables ( P > 0.05), e.g. age. Our results suggest that blood pressure variability is not a potential mechanism to explain the association between leukoaraiosis and poor outcome after acute stroke.

Processing speed and the relationship between Trail Making Test-B performance, cortical thinning and white matter microstructure in older adults.

Part B of the Trail Making Test (TMT-B) is widely used as a quick and easy to administer measure of executive dysfunction. The current study investigated the relationships between TMT-B performance, brain volumes, cortical thickness and white matter water diffusion characteristics in a large sample of older participants, before and after controlling for processing speed. Four hundred and eleven healthy, community-dwelling older adults who were all born in 1936 were assessed on TMT-B, 5 tests of processing speed, and provided contemporaneous structural and diffusion MRI data. Significant relationships were found between slower TMT-B completion times and thinner cortex in the frontal, temporal and inferior parietal regions as well as the Sylvian fissure/insula. Slower TMT-B completion time was also significantly associated with poorer white matter microstructure of the left anterior thalamic radiation, and the right uncinate fasciculus. The majority of these associations were markedly attenuated when additionally controlling for processing speed. These data suggest that individual differences in processing speed contribute to the associations between TMT-B completion time and the grey and white matter structure of older adults.

Impact of small vessel disease in the brain on gait and balance.

Gait and balance impairment is highly prevalent in older people. We aimed to assess whether and how single markers of small vessel disease (SVD) or a combination thereof explain gait and balance function in the elderly. We analysed 678 community-dwelling healthy subjects from the Lothian Birth Cohort 1936 at the age of 71-74 years who had undergone comprehensive risk factor assessment, gait and balance assessment as well as brain MRI. We investigated the impact of individual SVD markers (white matter hyperintensity - WMH, microbleeds, lacunes, enlarged perivascular spaces, brain atrophy) as seen on structural brain MRI and of a global SVD score on the patients' performance. A regression model revealed that age, sex, and hypertension significantly explained gait speed. Among SVD markers white matter hyperintensity (WMH) score or volume were additional significant and independent predictors of gait speed in the regression model. A similar association was seen with the global SVD score. Our study confirms a negative impact of SVD-related morphologic brain changes on gait speed in addition to age, sex and hypertension independent from brain atrophy. The presence of WMH seems to be the major driving force for SVD on gait impairment in healthy elderly subjects.

Permutation and parametric tests for effect sizes in voxel-based morphometry of gray matter volume in brain structural MRI.

Permutation testing has been widely implemented in voxel-based morphometry (VBM) tools. However, this type of non-parametric inference has yet to be thoroughly compared with traditional parametric inference in VBM studies of brain structure. Here we compare both types of inference and investigate what influence the number of permutations in permutation testing has on results in an exemplar study of how gray matter proportion changes with age in a group of working age adults. High resolution T1-weighted volume scans were acquired from 80 healthy adults aged 25-64years. Using a validated VBM procedure and voxel-based permutation testing for Pearson product-moment coefficient, the effect sizes of changes in gray matter proportion with age were assessed using traditional parametric and permutation testing inference with 100, 500, 1000, 5000, 10000 and 20000 permutations. The statistical significance was set at P<0.05 and false discovery rate (FDR) was used to correct for multiple comparisons. Clusters of voxels with statistically significant (PFDR<0.05) declines in gray matter proportion with age identified with permutation testing inference (N≈6000) were approximately twice the size of those identified with parametric inference (N=3221voxels). Permutation testing with 10000 (N=6251voxels) and 20000 (N=6233voxels) permutations produced clusters that were generally consistent with each other. However, with 1000 permutations there were approximately 20% more statistically significant voxels (N=7117voxels) than with ≥10000 permutations. Permutation testing inference may provide a more sensitive method than traditional parametric inference for identifying age-related differences in gray matter proportion. Based on the results reported here, at least 10000 permutations should be used in future univariate VBM studies investigating age related changes in gray matter to avoid potential false findings. Additional studies using permutation testing in large imaging databanks are required to address the impact of model complexity, multivariate analysis, number of observations, sampling bias and data quality on the accuracy with which subtle differences in brain structure associated with normal aging can be identified.